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Article ; Online: Targeting MAIT cells as a cellular adjuvant for humoral immunity: a new player in a very old game.

Provine, Nicholas M

2023 Volume 101, Issue 6, Page(s) 470–472

Abstract: In this article, I discuss recent work by Pankhurst et al. They found that MAIT cells can serve as a cellular adjuvant to boost immunity to a protein adjuvant. Intranasal co-administration of protein antigen with a strong MAIT cell ligand results in the ... ...

Abstract	In this article, I discuss recent work by Pankhurst et al. They found that MAIT cells can serve as a cellular adjuvant to boost immunity to a protein adjuvant. Intranasal co-administration of protein antigen with a strong MAIT cell ligand results in the the production of mucosal IgA and IgG antibody responses. This process is driven by MAIT cell-mediated maturation of migratory dendritic cells.
MeSH term(s)	Immunity, Humoral ; Mucosal-Associated Invariant T Cells ; Adjuvants, Immunologic ; Antibody Formation ; Administration, Intranasal ; Immunity, Mucosal ; Immunity, Cellular
Chemical Substances	Adjuvants, Immunologic
Language	English
Publishing date	2023-05-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	284057-1
ISSN	1440-1711 ; 0818-9641
ISSN (online)	1440-1711
ISSN	0818-9641
DOI	10.1111/imcb.12648
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Article ; Online: Adenovirus vector and mRNA vaccines: Mechanisms regulating their immunogenicity.

Provine, Nicholas M / Klenerman, Paul

European journal of immunology

2022 Volume 53, Issue 6, Page(s) e2250022

Abstract: Replication-incompetent adenovirus (Ad) vector and mRNA-lipid nanoparticle (LNP) constructs represent two modular vaccine platforms that have attracted substantial interest over the past two decades. Due to the COVID-19 pandemic and the rapid development ...

Abstract	Replication-incompetent adenovirus (Ad) vector and mRNA-lipid nanoparticle (LNP) constructs represent two modular vaccine platforms that have attracted substantial interest over the past two decades. Due to the COVID-19 pandemic and the rapid development of multiple successful vaccines based on these technologies, there is now clear real-world evidence of the utility and efficacy of these platforms. Considerable optimization and refinement efforts underpin the successful application of these technologies. Despite this, our understanding of the specific pathways and processes engaged by these vaccines to stimulate the immune response remains incomplete. This review will synthesize our current knowledge of the specific mechanisms by which CD8
MeSH term(s)	Humans ; mRNA Vaccines ; Pandemics ; COVID-19/prevention & control ; Genetic Vectors/genetics ; Adenoviridae/genetics
Chemical Substances	mRNA Vaccines
Language	English
Publishing date	2022-11-20
Publishing country	Germany
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.202250022
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Zs.A 489: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: MAIT Cells in Health and Disease.

Provine, Nicholas M / Klenerman, Paul

Annual review of immunology

2019 Volume 38, Page(s) 203–228

Abstract: Mucosal-associated invariant T (MAIT) cells have been attracting increasing attention over the last few years as a potent unconventional T cell subset. Three factors largely account for this emerging interest. Firstly, these cells are abundant in humans, ...

Abstract	Mucosal-associated invariant T (MAIT) cells have been attracting increasing attention over the last few years as a potent unconventional T cell subset. Three factors largely account for this emerging interest. Firstly, these cells are abundant in humans, both in circulation and especially in some tissues such as the liver. Secondly is the discovery of a ligand that has uncovered their microbial targets, and also allowed for the development of tools to accurately track the cells in both humans and mice. Finally, it appears that the cells not only have a diverse range of functions but also are sensitive to a range of inflammatory triggers that can enhance or even bypass T cell receptor-mediated signals-substantially broadening their likely impact in health and disease. In this review we discuss how MAIT cells display antimicrobial, homeostatic, and amplifier roles in vivo, and how this may lead to protection and potentially pathology.
MeSH term(s)	Animals ; Biomarkers ; Disease Susceptibility ; Homeostasis ; Host-Pathogen Interactions ; Humans ; Immunity, Mucosal ; Mucosal-Associated Invariant T Cells/immunology ; Mucosal-Associated Invariant T Cells/metabolism ; Mucous Membrane/immunology ; Mucous Membrane/metabolism ; Mucous Membrane/microbiology ; Signal Transduction ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism
Chemical Substances	Biomarkers
Language	English
Publishing date	2019-01-27
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	604953-9
ISSN	1545-3278 ; 0732-0582
ISSN (online)	1545-3278
ISSN	0732-0582
DOI	10.1146/annurev-immunol-080719-015428
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Article ; Online: Fine needle aspiration of human lymph nodes reveals cell populations and soluble interactors pivotal to immunological priming.

Provine, Nicholas M / Al-Diwani, Adam / Agarwal, Devika / Dooley, Kyla / Heslington, Amelia / Murchison, Andrew G / Garner, Lucy C / Sheerin, Fintan / Klenerman, Paul / Irani, Sarosh R

European journal of immunology

2024 Volume 54, Issue 5, Page(s) e2350872

Abstract: Lymph node (LN) fine needle aspiration (LN FNA) represents a powerful technique for minimally invasive sampling of human LNs in vivo and has been used effectively to directly study aspects of the human germinal center response. However, systematic deep ... ...

Abstract	Lymph node (LN) fine needle aspiration (LN FNA) represents a powerful technique for minimally invasive sampling of human LNs in vivo and has been used effectively to directly study aspects of the human germinal center response. However, systematic deep phenotyping of the cellular populations and cell-free proteins recovered by LN FNA has not been performed. Thus, we studied human cervical LN FNAs as a proof-of-concept and used single-cell RNA-sequencing and proteomic analysis to benchmark this compartment, define the purity of LN FNA material, and facilitate future studies in this immunologically pivotal environment. Our data provide evidence that LN FNAs contain bone-fide LN-resident innate immune populations, with minimal contamination of blood material. Examination of these populations reveals unique biology not predictable from equivalent blood-derived populations. LN FNA supernatants represent a specific source of lymph- and lymph node-derived proteins, and can, aided by transcriptomics, identify likely receptor-ligand interactions. This represents the first description of the types and abundance of immune cell populations and cell-free proteins that can be efficiently studied by LN FNA. These findings are of broad utility for understanding LN physiology in health and disease, including infectious or autoimmune perturbations, and in the case of cervical nodes, neuroscience.
MeSH term(s)	Humans ; Lymph Nodes/immunology ; Biopsy, Fine-Needle/methods ; Proteomics/methods ; Immunity, Innate ; Female ; Single-Cell Analysis/methods ; Germinal Center/immunology ; Male
Language	English
Publishing date	2024-02-22
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.202350872
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Zs.A 489: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article: Insights Into Mucosal-Associated Invariant T Cell Biology From Studies of Invariant Natural Killer T Cells.

Garner, Lucy C / Klenerman, Paul / Provine, Nicholas M

Frontiers in immunology

2018 Volume 9, Page(s) 1478

Abstract: Mucosal-associated invariant T (MAIT) cells and invariant natural killer T (iNKT) cells are innate-like T cells that function at the interface between innate and adaptive immunity. They express semi-invariant T cell receptors (TCRs) and recognize ... ...

Abstract	Mucosal-associated invariant T (MAIT) cells and invariant natural killer T (iNKT) cells are innate-like T cells that function at the interface between innate and adaptive immunity. They express semi-invariant T cell receptors (TCRs) and recognize unconventional non-peptide ligands bound to the MHC Class I-like molecules MR1 and CD1d, respectively. MAIT cells and iNKT cells exhibit an effector-memory phenotype and are enriched within the liver and at mucosal sites. In humans, MAIT cell frequencies dwarf those of iNKT cells, while in laboratory mouse strains the opposite is true. Upon activation
Language	English
Publishing date	2018-06-28
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606827-8
ISSN	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2018.01478
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Article ; Online: The HDAC inhibitor zabadinostat is a systemic regulator of adaptive immunity.

Liu, Geng / Barczak, Wojciech / Lee, Lian Ni / Shrestha, Amit / Provine, Nicholas M / Albayrak, Gulsah / Zhu, Hong / Hutchings, Claire / Klenerman, Paul / La Thangue, Nicholas B

Communications biology

2023 Volume 6, Issue 1, Page(s) 102

Abstract: Protein acetylation plays a key role in regulating cellular processes and is subject to aberrant control in diverse pathologies. Although histone deacetylase (HDAC) inhibitors are approved drugs for certain cancers, it is not known whether they can be ... ...

Abstract	Protein acetylation plays a key role in regulating cellular processes and is subject to aberrant control in diverse pathologies. Although histone deacetylase (HDAC) inhibitors are approved drugs for certain cancers, it is not known whether they can be deployed in other therapeutic contexts. We have explored the clinical HDAC inhibitor, zabadinostat/CXD101, and found that it is a stand-alone regulator of the adaptive immune response. Zabadinostat treatment increased expression of MHC class I and II genes in a variety of cells, including dendritic cells (DCs) and healthy tissue. Remarkably, zabadinostat enhanced the activity of DCs, and CD4 and CD8 T lymphocytes. Using an antigenic peptide presented to the immune system by MHC class I, zabadinostat caused an increase in antigen-specific CD8 T lymphocytes. Further, mice immunised with covid19 spike protein and treated with zabadinostat exhibit enhanced covid19 neutralising antibodies and an increased level of T lymphocytes. The enhanced humoral response reflected increased activity of T follicular helper (Tfh) cells and germinal centre (GC) B cells. Our results argue strongly that zabadinostat has potential to augment diverse therapeutic agents that act through the immune system.
MeSH term(s)	Mice ; Animals ; Immunity, Humoral ; T-Lymphocytes, Helper-Inducer ; Histone Deacetylase Inhibitors/pharmacology ; COVID-19 ; Adaptive Immunity ; Antigens
Chemical Substances	Histone Deacetylase Inhibitors ; Antigens
Language	English
Publishing date	2023-01-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-023-04485-y
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Article ; Online: Single-cell analysis of human MAIT cell transcriptional, functional and clonal diversity.

Garner, Lucy C / Amini, Ali / FitzPatrick, Michael E B / Lett, Martin J / Hess, Gabriel F / Filipowicz Sinnreich, Magdalena / Provine, Nicholas M / Klenerman, Paul

Nature immunology

2023 Volume 24, Issue 9, Page(s) 1565–1578

Abstract: Mucosal-associated invariant T (MAIT) cells are innate-like T cells that recognize microbial metabolites through a semi-invariant T cell receptor (TCR). Major questions remain regarding the extent of human MAIT cell functional and clonal diversity. To ... ...

Abstract	Mucosal-associated invariant T (MAIT) cells are innate-like T cells that recognize microbial metabolites through a semi-invariant T cell receptor (TCR). Major questions remain regarding the extent of human MAIT cell functional and clonal diversity. To address these, we analyzed the single-cell transcriptome and TCR repertoire of blood and liver MAIT cells and developed functional RNA-sequencing, a method to integrate function and TCR clonotype at single-cell resolution. MAIT cell clonal diversity was comparable to conventional memory T cells, with private TCR repertoires shared across matched tissues. Baseline functional diversity was low and largely related to tissue site. MAIT cells showed stimulus-specific transcriptional responses in vitro, with cells positioned along gradients of activation. Clonal identity influenced resting and activated transcriptional profiles but intriguingly was not associated with the capacity to produce IL-17. Overall, MAIT cells show phenotypic and functional diversity according to tissue localization, stimulation environment and clonotype.
MeSH term(s)	Humans ; Mucosal-Associated Invariant T Cells ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/metabolism ; Clone Cells/metabolism ; Lymphocyte Activation/genetics ; Single-Cell Analysis
Chemical Substances	Receptors, Antigen, T-Cell
Language	English
Publishing date	2023-08-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/s41590-023-01575-1
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Article: Novel Concepts for HIV Vaccine Vector Design.

Alayo, Quazim A / Provine, Nicholas M / Penaloza-MacMaster, Pablo

mSphere

2017 Volume 2, Issue 6

Abstract: The unprecedented challenges of developing effective vaccines against intracellular pathogens such as HIV, malaria, and tuberculosis have resulted in more rational approaches to vaccine development. Apart from the recent advances in the design and ... ...

Abstract	The unprecedented challenges of developing effective vaccines against intracellular pathogens such as HIV, malaria, and tuberculosis have resulted in more rational approaches to vaccine development. Apart from the recent advances in the design and selection of improved epitopes and adjuvants, there are also ongoing efforts to optimize delivery platforms. Viral vectors are the best-characterized delivery tools because of their intrinsic adjuvant capability, unique cellular tropism, and ability to trigger robust adaptive immune responses. However, a known limitation of viral vectors is preexisting immunity, and ongoing efforts are aimed at developing novel vector platforms with lower seroprevalence. It is also becoming increasingly clear that different vectors, even those derived from phylogenetically similar viruses, can elicit substantially distinct immune responses, in terms of quantity, quality, and location, which can ultimately affect immune protection. This review provides a summary of the status of viral vector development for HIV vaccines, with a particular focus on novel viral vectors and the types of adaptive immune responses that they induce.
Language	English
Publishing date	2017-11
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2379-5042
ISSN	2379-5042
DOI	10.1128/mSphere.00415-17
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Article ; Online: CMV-associated T cell and NK cell terminal differentiation does not affect immunogenicity of ChAdOx1 vaccination.

Sharpe, Hannah R / Provine, Nicholas M / Bowyer, Georgina S / Moreira Folegatti, Pedro / Belij-Rammerstorfer, Sandra / Flaxman, Amy / Makinson, Rebecca / Hill, Adrian Vs / Ewer, Katie J / Pollard, Andrew J / Klenerman, Paul / Gilbert, Sarah / Lambe, Teresa

JCI insight

2022 Volume 7, Issue 6

Abstract: Cytomegalovirus (CMV) is a globally ubiquitous pathogen with a seroprevalence of approximately 50% in the United Kingdom. CMV infection induces expansion of immunosenescent T cell and NK cell populations, with these cells demonstrating lower ... ...

Abstract	Cytomegalovirus (CMV) is a globally ubiquitous pathogen with a seroprevalence of approximately 50% in the United Kingdom. CMV infection induces expansion of immunosenescent T cell and NK cell populations, with these cells demonstrating lower responsiveness to activation and reduced functionality upon infection and vaccination. In this study, we found that CMV+ participants had normal T cell responses after a single-dose or homologous vaccination with the viral vector chimpanzee adenovirus developed by the University of Oxford (ChAdOx1). CMV seropositivity was associated with reduced induction of IFN-γ-secreting T cells in a ChAd-Modified Vaccinia Ankara (ChAd-MVA) viral vector vaccination trial. Analysis of participants receiving a single dose of ChAdOx1 demonstrated that T cells from CMV+ donors had a more terminally differentiated profile of CD57+PD1+CD4+ T cells and CD8+ T cells expressing less IL-2Rα (CD25) and fewer polyfunctional CD4+ T cells 14 days after vaccination. NK cells from CMV-seropositive individuals also had a reduced activation profile. Overall, our data suggest that although CMV infection enhances immunosenescence of T and NK populations, it does not affect antigen-specific T cell IFN-γ secretion or antibody IgG production after vaccination with the current ChAdOx1 nCoV-19 vaccination regimen, which has important implications given the widespread use of this vaccine, particularly in low- and middle-income countries with high CMV seroprevalence.
MeSH term(s)	ChAdOx1 nCoV-19 ; Cytomegalovirus ; Cytomegalovirus Infections ; Humans ; Killer Cells, Natural ; Seroepidemiologic Studies ; Vaccination
Chemical Substances	ChAdOx1 nCoV-19 (B5S3K2V0G8)
Language	English
Publishing date	2022-03-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.154187
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Article: Memory inflation following adenoviral vaccination depends on IL-21

Gordon, Claire L / Hutchings, Claire L / Highton, Andrew J / Colston, Julia M / Provine, Nicholas M / Klenerman, Paul

Vaccine. 2018 Nov. 12, v. 36, no. 46

2018

Abstract: Cytomegalovirus (CMV) and non-replicating adenoviral vectors can induce expanded, sustained effector-memory CD8+ T-cell responses, termed “memory inflation”. During murine CMV (MCMV) infection, CD4+ Tcells maintain inflationary virus-specific CD8+ T-cell ...

Abstract	Cytomegalovirus (CMV) and non-replicating adenoviral vectors can induce expanded, sustained effector-memory CD8+ T-cell responses, termed “memory inflation”. During murine CMV (MCMV) infection, CD4+ Tcells maintain inflationary virus-specific CD8+ T-cell responses via IL-2 but not IL-21. Adenovirus vector vaccination can induce phenotypically, functionally and transcriptionally similar inflationary responses, but it is not known how IL-21 influences the inflating memory response to adenoviral vaccination. Here, we show that IL-21 is an absolute requirement for induction and maintenance of vaccine-derived inflationary CD8+ T-cell responses. These data indicate that the induction pathway of inflationary Ad-LacZ T-cells is distinct from inflationary MCMV-specific T-cells and is highly dependent on IL-21. Our observations highlight a fundamental difference in the mechanism by which adenovirus vectors and MCMV drive inflationary T-cell responses.
Keywords	Adenoviridae ; CD8-positive T-lymphocytes ; Cytomegalovirus ; interleukin-2 ; interleukin-21 ; memory ; mice ; transcription (genetics) ; vaccination ; vaccines
Language	English
Dates of publication	2018-1112
Size	p. 7011-7016.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	605674-x
ISSN	1873-2518 ; 0264-410X
ISSN (online)	1873-2518
ISSN	0264-410X
DOI	10.1016/j.vaccine.2018.09.061
Database	NAL-Catalogue (AGRICOLA)

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